The invention relates to a process for the production of N-.beta.-hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-.beta.-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetrade cane derivatives and their metal complexes.
Because of their importance for the production of imaging diagnostic agents (DE OS 36 25 417), especially NMR diagnostic agents, the production of N-.beta.-hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-.beta.-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetrade cane derivatives has been tried in the many various ways without finding a satisfactory method of synthesis, especially for production on an industrial scale.
For the synthesis of tetraazamacrocycles (1,4,7,10-tetraazacyclododecane derivatives or 1,4,8,11-tetraazacyclotetradecane derivatives) with the above-mentioned substitution pattern, basically three different methods are followed in the prior art:
1) A start is made from two reactants, which are cyclized to the tetraazamacrocycle according to methods known in the literature [e.g., Richman, Org. Synthesis 58, 86 (1978); Atkins, J. Amer. Chem. Soc. 96, 2268 (1974)]. One of the two reactants contains a protected nitrogen atom and carries on the chain end two leaving groups (e.g., bromine, mesyloxy, tosyloxy, triflate or alkoxycarbonyl groups), which are nucleophilically displaced from the terminal nitrogen atoms of the second reactant, a protected triaza compound whose protecting groups are distinguished from the protecting group of the first reactant. A tetra-substituted tetraazamacrocycle with three identical protecting groups and one protecting group different therefrom is thus obtained. The protecting groups can be specifically cleaved and the desired substituents are introduced. As an example, the reaction of the disodium salt of N,N',N"-tris(p-tolylsulfonyl)diethylenetriamine [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984)] with N-bis-(2-methanesulfonyloxyethyl)triphenylmethylamine in dimethylformamide at 80.degree.-150.degree. C. with subsequent cleavage of the trityl group under acidic conditions can be mentioned. The yields of both reaction stages are generally poor. After the subsequent specific monosubstitution for the introduction of substituent R.sup.2 [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984); Kaden, Helv. Chim. [Swiss Chem.] Acta 66, 861 (1983); Basefield, Inorg. Chem. 25, 4663 (1986)], the protecting groups are removed on three nitrogen atoms, e.g., by alkali metal in ammonia [Helv. Chim. Acta, ,56, 2216 (1973); Helv. Chim. Acta 59, 1566 (1976); J. Org. Chem. 53, 3521 (1988)], lithium aluminum hydride [F. Vogle, Liebigs Ann. Chem. 1344 (1977)], Red.-Al.RTM. [E. H. Gold, J. Org. Chem. 37, 2208, (1972)], Na--Hg [M. Kellog, J. Org. Chem. 49, 110 (1984)], electrolysis [M. Hesse, Helv. Chim. Acta 71 (1988), 7, 1708] or hydrobromic acid/phenol/glacial acetic acid [N. G. Lukyanenko, Synthesis, 1988, 355]. Subsequent trialkylation with haloacetic acid derivatives finally results in a tetrasubstituted tetraazamacrocycle. The above-indicated processes of the protecting group cleavage are generally connected with poor yields, limits on the batch size with respect to the amount of reagent to be used (e.g., in the sodium-amalgam method) and above all cannot be used in the case of substituents which carry sensitive groups (e.g., hydroxyalkyl). PA1 2) By statistical trisubstitution of the unprotected tetraazamacrocycle, a tetraazamacrocycle substituted with three identical radicals (e.g., tosyl, benzoyl, carboxyethyl radical) is obtained in another process. Monosubstituted and disubstituted products also result, which have to be separated by selective precipitation, chromatography and crystallization (EP 232 751, EP 292 689). In both European patent applications, a yield of about 23% is obtained in the stage of the statistical trisubstitution. This means that 77% of the very expensive starting material 1,4,7,10tetraazacyclododecane is lost. The subsequent stages can then follow as already described under 1). All drawbacks of a statistical reaction known to one skilled in the art, such as the above-indicated low yields and separation problems (above all in the production of substantial amounts of substances) make this process appear to be nonadvantageous. PA1 3) Tweedle et al. describe in European patent application 292 689 that starting from the unsubstituted macrocyclic compound 1,4,7,10-tetraazacyclododecane, the N-formyl compound can be obtained by a tricyclic intermediate stage. This compound still carrying three unprotected nitrogen atoms can now be trialkylated, deformylated and converted to the tetrasubstituted tetraazamacrocycle with haloacetic ester derivatives. But the number of reaction steps to the tris-carboxymethyl-monoalkyl-tetraazamacrocycle is also highly unsatisfactory in this process. Also, it has been shown that the tricyclic intermediate stage is extremely sensitive toward water, alcohol and dimethylformamide. These substances cannot be removed completely enough in large batches, which leads to yield losses, which jeopardize the usability of the process on an industrial scale. PA1 R.sup.3 is hydrogen, C.sub.1 -C.sub.6 -alkyl, benzyl, benzyloxyalkyl or phenyl, PA1 Y is, in each case, hydrogen or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, ##STR2## n is, in each case, 2 or 3, R.sup.4 R.sup.5 independent of one another, are each hydrogen, C.sub.1 -C.sub.20 -alkyl optionally interrupted by 1 to 10 oxygen atoms, a phenylene, phenylenoxy or phenylenedioxy group, which optionally is substituted by 1 to 3 C.sub.1 -C.sub.6 -alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 C.sub.1 -C.sub.7 -alkoxy, 1 to 3 C.sub.7 -C.sub.10 -aralkoxy, 1 to 2 CO.sub.2 R.sup.6 radicals, and/or 1 to 2 phenoxy or phenyl groups optionally substituted by 1 to 2 chloro, bromo, nitro or C.sub.1 -C.sub.6 -alkoxy radicals, PA1 R.sup.6 is hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.6 -C.sub.10 -aryl , or C.sub.6 -C.sub.10 --Ar(C.sub.1 -C.sub.4)alkyl, and PA1 the optionally present hydroxy radicals or carboxy groups optionally are present in protected form, PA1 the impurities are separated, optionally, if necessary after adding acids, the resultant product is isolated, and reacted, optionally in the presence of a base, with a compound of formula III ##STR4## wherein R.sup.3 and R.sup.6 have the above-indicated meanings, PA1 X is a leaving group, and PA1 o and p, independent of one another, are each a number 0 to 5, wherein the sum o+p is less than 6, PA1 optionally after protection of hydroxy or carboxy groups in R.sup.2, in a polar solvent at about -10.degree. C. to 170.degree. C. within about 1-100 hours, PA1 protecting groups are optionally cleaved, the thus obtained product of formula I, in which each Y is hydrogen, is then optionally reacted in a way known in the art with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, and, PA1 if desired, still present acidic hydrogen atoms are substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides, or the corresponding acid groups are converted, completely or partially, to esters or amides. The thus obtained complex can then be isolated. PA1 1) The use of nitrogen protecting groups is completely avoided; PA1 2) The tetraazamacrocycles, which carry sensitive groups, such as, e.g., hydroxy groups, can be produced by this process on an industrial scale; PA1 3) The extraction steps, following reaction with the epoxide of formula II, make possible a complete separation of by-products, so that expensive chromatographic separations or selective precipitations are eliminated; PA1 4) The process according to the invention results in a considerably lower number of steps to obtain the tetra-substituted macrocycle than the processes of the prior art; and PA1 5) In the first reaction step, at most one equivalent macrocycle is used relative to epoxide and the substitution product is obtained in high yields; thus, a greater loss of the very expensive starting material 1,4,7,10-tetraazacyclododecane is avoided. PA1 --CH.sub.2 --O--C.sub.11 H.sub.22 --OH, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --O--(CH.sub.2 CH.sub.2 O).sub.2 --CH.sub.3, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --O--(CH.sub.2 CH.sub.2 O).sub.3 --C.sub.5 H.sub.11, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --O--C.sub.4 H.sub.8 --OH, PA1 --(CH.sub.2 CH.sub.2 O).sub.5 --CH.sub.3, PA1 --C.sub.9 H.sub.18 --COOH, PA1 --C.sub.9 H.sub.18 --OH, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --O--C.sub.6 H.sub.12 --COOH, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --O--C.sub.4 H.sub.8 --O--CH.sub.2 --CHOH--CH.sub.2 OH, PA1 --(CH.sub.2 CH.sub.2 O).sub.3 --C.sub.5 H.sub.11, PA1 --CH.sub.2 --O--C.sub.10 H.sub.20 --COOH, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --Cl, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --NO.sub.2, PA1 --CH.sub.2 --O--C.sub.6 H.sub.3 Cl.sub.2, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --COOH, PA1 --CHOH--CH.sub.2 OH, PA1 --CH.sub.2 --O--CH.sub.2 --CHOH--CH.sub.2 OH, PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --O--CH.sub.2 --COOH, and PA1 --CH.sub.2 --O--C.sub.6 H.sub.4 --C.sub.5 H.sub.11.
Thus, it has not been possible to find a satisfactory synthesis method for the desired tetrasubstituted tetraazamacrocycles, which are to be considered as key compounds for the tri-N-carboxyalkyl-metal complexes being used, e.g., as valuable NMR and x-ray contrast media.
Because of the high demand for NMR and x-ray contrast media and the above-mentioned drawbacks of the prior art, there therefore still exists the need for a process for the production of these media, which is suitable above all for the reaction of greater substance amounts. An object of the invention is to provide such a process.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
These objects are achieved by the inventive process.
It has been found that surprisingly N-.beta.-hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-.beta.-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetrade cane derivatives of general formula I ##STR1## wherein R.sup.1 is --(CH.sub.2).sub.1-6 --COOY optionally substituted by R.sup.3,
can be obtained by reacting 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane, optionally in the form of their salts, in the presence of a base with an epoxide of formula II ##STR3## wherein R.sup.4 and R.sup.5 have the above-indicated meanings, and optionally present hydroxy or carboxy groups are optionally protected, in a polar solvent or without solvent at temperatures of about 0.degree. C.-220.degree. C., preferably room temperature e.g., about 20.degree. C.) to 200.degree. C., especially 50.degree. C. to 150.degree.C., within about 0.5-48 hours,
The process according to the invention is distinguished with respect to the prior art by several decisive advantages:
The R.sup.1 carboxyalkyl group can be unbranched or branched, and unbranched carboxyalkyl groups are preferred. The length of the alkyl chain can be 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms.
As alkyl groups for R.sup.6 and R.sup.3 with 1-6 carbon atoms, straight-chain or branched alkyl groups are suitable, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. Methyl, ethyl, and tert-butyl are especially preferred.
Preferred radicals for R.sup.4 and R.sup.5 are hydrogen, methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 1-(hydroxymethyl)ethyl, propyl, isopropyl, isopropenyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, butyl, isobutyl, isobutenyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-2-methylbutyl, 3-hydroxy-2-methylbutyl, 4-hydroxy-2-methylbutyl, 2-hydroxyisobutyl, 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl, 1,2,4-trihydroxybutyl, pentyl, cyclopentyl, 2-methoxyethyl, hexyl, decyl, tetradecyl, triethylene glycol methyl ether, tetraethylene glycol methyl ether and methoxybenzyl as well as the
Preferably, R.sup.4 and R.sup.5 are each, independent of one another, hydrogen, C.sub.1 -C.sub.4 -alkyl, or C.sub.1 -C.sub.4 -alkyl substituted by 1-4 hydroxy groups. Especially preferred groups for R.sup.4 are hydrogen, methyl and hydroxymethyl and for R.sup.5 are methyl, hydroxymethyl, and 1,2-dihydroxymethyl.
Preferred aryl groups and aralkyl groups R.sup.6 are phenyl, naphthyl and benzyl.
Especially preferred radicals R.sup.6 are hydrogen, methyl or benzyl.
Especially preferred radicals R.sup.3 are hydrogen, C.sub.1 -C.sub.3 -alkyl or benzyloxymethyl.
In the epoxide compound of formula II, optionally present carboxyl and/or hydroxy groups are present preferably in protected form.
Acid protecting groups, which can also stand for R.sup.6, include C.sub.1 -C.sub.6 -alkyl, C.sub.6 -C.sub.10 -aryl and C.sub.6 -C.sub.10 --Ar(C.sub.1 -C.sub.4)alkyl groups, for example, the methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, and benzyl. Diphenylmethyl, triphenylmethyl, bis (p-nitrophenyl) -methyl group, as well as trialkylsilyl groups, are also suitable acid protecting groups.
The cleavage of the protecting groups takes place according to the processes known to one skilled in the art, for example, by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous alcoholic solution at temperatures of 0.degree. to 50.degree. C., acid saponification with mineral acids or in the case of, e.g., tert-butyl esters with the help of trifluoroacetic acid.
As hydroxy protecting groups, e.g., the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl, diphenyl-t-butylsilyl groups are suitable.
The hydroxy groups can also be present, e.g., as THP ether, .alpha.-alkoxyethyl ether, MEM ether or as esters with aromatic or aliphatic carboxylic acids, such as, e.g., acetic acid or benzoic acid. In the case of polyols, the hydroxy groups can also be protected in the form of ketone acetals with, e.g., acetone, acetaldehyde, cyclohexanone or benzaldehyde.
The hydroxy protecting groups can be released according to the literature methods known to one skilled in the art, e.g., by hydrogenolysis, reductive cleavage with lithium/ammonia, acid treatment of the ethers and ketone acetals or alkali treatment of the esters (see, e.g., "Protective Groups in Organic Synthetics," T. W. Greene, John Wiley and Sons 1981).
Every leaving group familiar to one skilled in the art can stand for leaving group X. For example, acetate, brosylate, mesylate, nosylate, tosylate, trifluoroacetate, trifluorosulfonate, chlorine, bromine or iodine can be mentioned. Preferred leaving groups are chlorine and bromine, especially preferred is chlorine.
As the starting compound, the macrocyclic compounds 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane or their salts are used for the process according to the invention.
As salt formers, all inorganic and organic acids are suitable which form stable salts with the above-mentioned macrocycles. For example, phosphoric acid, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid can be mentioned.
In a preferred process, the above-mentioned macrocycles are used as hydrochlorides or as sulfates. These can be obtained according to processes known in the literature. The sulfate can be obtained, e.g., according to Organic Synthesis, Vol. 58, 89, 1978. But it is designated as "polyhydrosulfate" in the literature, whose content has to be determined by sulfur determination after each batch. The content fluctuates between 3 and 4 equivalents of sulfuric acid.
The tetrahydrochloride can be obtained according to J. Amer. Chem. Soc., 96, 2268, (1974) or according to Recueil des Traveaux de Pays Bas [Collection of Works of the Netherlands], 110, 124, (1991).
The molar ratio of macrocycle to epoxide is preferably 1:1 to 1:2 according to the process of the invention, and an excess of epoxide is especially preferred (e.g., 1:1.2, 1:1.4 or 1:1.5).
The base added in the reaction of the macrocycle with the epoxide of formula II ##STR5## can be one of the usual inorganic or organic bases known to one skilled in the art such as, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, pyridine or N,N-dimethylaminopyridine. Potassium hydroxide, sodium hydroxide, lithium hydroxide are preferably used, sodium hydroxide is especially preferably used.
If the reaction is to be performed without solvent, the free macrocyclic compound has to be reacted. The latter can be obtained, e.g., analogously to Helv. Chim. Acta, 66, 863 (1983) from the sulfate by base treatment.
As solvents, polar aprotic solvents, such as, e.g., acetonitrile, diethyl carbonate, diethyl ether, dimethylacetamide, dimethyl sulfoxide, dioxane, N-methylpyrrolidone, tetrahydrofuran or tetramethylurea and their mixtures as well as protic solvents, such as, for example, alcohols with 1-8 C atoms, are suitable. Methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, for example, can be mentioned.
If the solvents used for this reaction are water-miscible, they are removed by distillation after the end of the reaction before an extraction.
With sufficient solubility of the reactants, relatively nonpolar aprotic solvents, such as, for example, benzene, toluene or hydrocarbons, such as, for example, n-hexane, can also be used for the reactions.
The reaction with the epoxide of formula II is performed at temperatures between 0.degree.-220.degree. C., preferably between room temperature and 200.degree. C., especially preferably between 50.degree. C. and 150.degree. C. The reaction time in each corresponding temperature interval is 1 to 48 (e.g., 5 to 48), preferably 1 to 24 (e.g., 5 to 24), especially preferably 1 to 6, hours.
The purification of the monoalkylation product performed after the end of the reaction can take place, e.g., by extraction, optionally in several stages.
It is an advantage of the process according to the invention that the isolation of the monoalkylation product is not necessary.
But if the cleavage of protecting groups and/or an isolation of the monoalkylation product is desired, it advantageous to add mineral acids or organic acids, such as, for example, hydrochloric acid, sulfuric acid, formic acid, acetic acid or trifluoroacetic acid.
The following reaction to introduce the three carboxyalkyl groups takes place by reaction with a compound of general formula III ##STR6## in polar solvents, such as, for example, acetonitrile, acetone, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, tetrahydrofuran or water or in alcohols with a chain length with up to 8 C atoms, as they have already been described for the first reaction. Dimethylformamide and water are preferred.
The reaction is performed at temperatures of -10.degree. C.-170.degree. C., preferably at 0.degree.-120.degree. C., especially preferably at 40.degree.-100.degree. C.
The reaction time is about 1-100 hours, preferably 1-30 hours, especially preferably 3-12 hours.
In an especially preferred process, the compound of formula III is chloroacetic acid.
The bases added as acid traps in the reaction with the compound of formula III can be tertiary amines (for example, triethylamine, trimethylamine, N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]-nonene-5(DBN), 1,5-diazabicyclo[5.4.0]-undecene-5-(DBU)), alkali or alkaline-earth carbonates, bicarbonates or hydroxides (for example, lithium, sodium potassium, magnesium, calcium, barium, -carbonate, -hydroxide and -bicarbonate). Sodium hydroxide is especially preferably used.
The optionally necessary introduction or cleavage of protecting groups of the carboxyl or hydroxy functions takes place according to the methods already mentioned for the first process step.
The production of the metal complexes according to the invention takes place in the way as it has been disclosed in German laid-open specification 34 01 052, by the metal oxide or a metal salt (for example, the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83 being dissolved or suspended in water and/or a lower alcohol (such as, methanol, ethanol or isopropanol) and reacted with the solution or suspension of the equivalent amount of the complexing ligand and then, if desired, present acidic hydrogen atoms being substituted by cations of inorganic and/or organic bases or amino acids.
The introduction of the desired metal ions can take place in this connection both before and after the cleavage of the protecting groups for the optionally present hydroxy or other functional groups.
The neutralization of optionally still present free carboxy groups takes place with the help of inorganic bases (for example, hydroxides, carbonates or bicarbonates) of, for example, lithium, sodium, potassium, magnesium or calcium and/or organic bases, such as, i.a., primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methylamine and N,N-dimethylamine, as well as basic amino acids, such as, for example, lysine, arginine and ornithine or of amides of originally neutral or acid amino acids.
For the production of neutral complex compounds, enough of the desired bases can be added, for example, to the acid complex salts in aqueous solution or suspension that the point of neutrality is reached. The obtained solution can then be evaporated to dryness in a vacuum. Often, it is advantageous to precipitate the formed neutral salts by adding water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others and thus to obtain crystallizates that are easy to isolate and easy to purify. It has proven especially advantageous to add the desired base already during the complexing of the reaction mixture and thus to save a process step.
If the acid complex compounds contain several free acidic groups, it is often suitable to produce neutral mixed salts, which contain both inorganic and organic cations as counterions.
This can happen, for example, by the complexing ligands being reacted in aqueous suspension or solution with the oxide or salt of the element yielding the metal ion and half of the amount of an organic base necessary for neutralization, the formed complex salt being isolated, it being optionally purified and then mixed with the necessary amount of inorganic base for complete neutralization. The sequence of the addition of base can also be reversed.
Another possibility, to achieve neutral complex compounds, consists in converting the remaining acid groups in the complex completely or partially into, for example, esters or amides. This can happen by additional reaction on the completed complex (for example, by exhaustive reaction of the free carboxy groups with dimethyl sulfate). If the remaining acid groups are converted only partially to esters or amides, the free acid groups then still remaining can be converted to their salts as described above.
The following embodiments are used to explain this invention, but they are not to limit it.
For the ion exchange chromatography, various embodiments of the product Amberlite.RTM. of the Rohm & Haas company are used.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications cited above and of corresponding German application P 42 18 744.3, are hereby incorporated by reference.